The nature and contribution of the immune system to the pathogenesis of periodontal disease (PD) remains unclear. Several studies suggest that the immune system has undesirable effects and contributes to the disease process while others propose that it plays a primary role to minimize or prevent disease. To better define the role of the host's immune system in the pathogenesis of PD, we propose to develop and apply the severe combined immunodeficient (SCID) mouse model to study human immune responses to periodontal pathogens. SCID mice lack a functional immune system and, therefore, accept xenogeneic grafts. In preliminary studies, we have demonstrated that SCID mice reconstituted with cells from patients with localized juvenile periodontitis (SCID-LJP) develop a functional immune system with a repertoire similar to that of the human donor. The fundamental hypothesis to be tested is that the immune system plays a protective role to prevent or retard periodontal infection. Specifically, we propose that induction of an immune response capable of neutralizing factors that may promote bacterial virulence will enhance host resistance to disease. The study is divided into three specific aims: (1) To develop and optimize the SCID mouse model for the analysis of the human immune response to Actinobacillus actinomycetemcomitans. (2) To determine if individual A. actinomycetemcomitans antigens are capable of augmenting protective immunity in SCID-LJP mice. Three groups of antigens will be employed: potential virulence factors (leukotoxin, immunosuppressive factor and fibroblast inhibitory factor), the immunodominant antigen (LPS) and outer membrane proteins. (3) To further define the host response to LTX and identify subregions, components and/or epitopes of LTX and LPS that are responsible for augmentation of protective immunity in SCID-LJP mice. Collectively, these studies will further our understanding of the role of the immune response in PD by helping to define the nature, specificity and adaptability of the human immune response to A. actinomycetemcomitans. Furthermore, this investigation may provide a foundation for the future development of vaccines to retard and prevent periodontal disease.